β2-adrenergic signaling drives GRAMD1B induction and MYC regulatory remodeling in catecholamine-induced endothelial dysfunction

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Sustained elevations of circulating catecholamines are associated with endothelial injury and adverse outcomes in acute critical illness, yet the endothelial-intrinsic molecular response to prolonged adrenergic stimulation remains poorly defined. Understanding how endothelial cells integrate adrenergic signaling into stress responses is essential for clarifying mechanisms of catecholamine-driven endothelial dysfunction. We combined phenotypic assays with transcriptomic and proteomic profiling to define endothelial stress responses to catecholamine exposure in human lung microvascular endothelial cells and used pharmacologic receptor blockade to assess receptor-specific signaling contributions. Catecholamine exposure induced loss of barrier integrity, metabolic activation, and increased expression of endothelial injury markers, including thrombomodulin and syndecan-1. Biochemical profiling revealed time- and dose-dependent remodeling of pathways linked to mitochondrial metabolism, oxidative stress, and lipid handling. GRAMD1B emerged as the only gene showing both dose-responsive and temporally persistent induction. Transcriptional regulator analysis highlighted MYC as a recurrent regulatory feature, and catecholamine exposure reduced Ser62-phosphorylated MYC relative to total MYC, indicating altered MYC regulatory control. Selective β2-adrenergic inhibition, in contrast to α1-adrenergic blockade, attenuated key molecular responses, including induction of endothelial injury marker thrombomodulin, GRAMD1B upregulation, and alterations in MYC regulatory state, supporting β2-adrenergic signaling as a major contributor to the endothelial stress response. These findings describe a coordinated endothelial stress response to β2-adrenergic signaling, encompassing metabolic remodeling, transcriptional changes, and barrier dysfunction. GRAMD1B induction and MYC regulatory remodeling emerged as consistent and parallel molecular features of catecholamine-driven endothelial stress. These results provide a molecular framework for understanding endothelial responses to sustained adrenergic stimulation.

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